This application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsins B, K, L or S.
Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g., as a result of increase expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, peeiodontal disease, metachromatic leukodystrophy and others. For example, increased cathepsin B levels and redistribution of the enzyme are found in tumors; thus, suggesting a role for the enzyme in tumor invasion and metastasis. In addition, aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.
The prominent expression of cathepsin K in osteoclasts and osteoclast-related multinucleated cells and its high collagenolytic activity suggest that the enzyme is involved in ososteoclast-mediated bone resorption and, hence, in bone abnormalities such as occurs in osteoporosis. In addition, cathepsin K expression in the lung and its elastinolytic activity suggest that the enzyme plays a role in pulmonary disorders as well.
Cathepsin L is implicated in normal lysosomal proteolysis as well as several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer""s disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves"" disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto""s thyroiditis; allergic disorders, including, but not limited to asthma; and allogeneic immune responses, including, but not limited to, rejection of organ transplants or tissue grafts.
In view of the number of diseases wherein it is recognized that an increase in cysteine protease activity contributes to the pathology and/or symptomatology of the disease, molecules which are shown to inhibit the activity of this class of enzymes, in particular molecules which are inhibitors of cathepsins B, K, L and/or S, will be useful as therapeutic agents.
This Application relates to compounds of Formula I: 
in which:
R1 is a group of Formula (a) or (b): 
xe2x80x83wherein:
X1 and X2 independently are xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2S(O)2xe2x80x94;
R5 and R6 independently are hydrogen, (C1-6)alkyl or as defined below;
R7 and R8 independently are hydrogen or (C1-6)alkyl or as defined below;
R9 and R10 independently are (i) (C1-6)alkyl optionally substituted with cyano, halo, halo-substituted (C1-3)alkyl, nitro, xe2x80x94NR12R12, xe2x80x94NR12C(O)OR12, xe2x80x94NR12C(O)NR12R12, xe2x80x94NR12C(NR12)NR12R12, xe2x80x94OR12, xe2x80x94SR12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94C(O)NR12R12, xe2x80x94S(O)2NR12R12, xe2x80x94P(O)(OR12)OR12, xe2x80x94OP(O)(OR12)OR12, xe2x80x94NR12C(O)R13, xe2x80x94S(O)R13, xe2x80x94S(O)2R13, xe2x80x94C(O)R13, xe2x80x94OR14, xe2x80x94SR14, xe2x80x94S(O)R14, xe2x80x94S(O)2R14, xe2x80x94C(O)R14, xe2x80x94C(O)OR14, xe2x80x94OC(O)R14, xe2x80x94NR14R15, xe2x80x94NR15C(O)R14, xe2x80x94NR15C(O)OR14, xe2x80x94C(O)NR14R15, xe2x80x94S(O)2NR14R15, xe2x80x94NR15C(O)NR14R15 or xe2x80x94NR15C(NR15)NR14R15, wherein R12 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl, R13 is (C1-6)alkyl or halosubstituted (C1-3)alkyl, R14 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl and R15 is hydrogen or (C1-6)alkyl, and wherein within R14 said cycloalkyl, heterocycloalkyl, aryl, heteroary, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R16, xe2x80x94X3OR16, xe2x80x94X3SR16, xe2x80x94X3S(O)R16, xe2x80x94X3S(O)2R16, xe2x80x94X3C(O)R16, xe2x80x94X3C(O)OR16, xe2x80x94X3OC(O)R16, xe2x80x94X3NR16R17, xe2x80x94X3NR17C(O)R16, xe2x80x94X3NR17C(O)OR16, xe2x80x94X3C(O)NR16R17, xe2x80x94X3S(O)2NR16R17, xe2x80x94X3NR17C(O)NR16R17 or xe2x80x94X3NR17C(NR17)NR16R17, wherein X3 is a bond or (C1-6)alkylene, R16 is hydrogen or (C1-6)alkyl and R17 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl, or (ii) a group selected from (C3-12)Cycloalkyl(C0-6)alky), hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl and hetero(C8-12)polycycloaryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R16, xe2x80x94X3OR16, xe2x80x94X3SR16, xe2x80x94X3S(O)R16, xe2x80x94X3S(O)2R16, xe2x80x94X3C(O)R16, xe2x80x94X3C(O)OR16, xe2x80x94X3OC(O)R16, xe2x80x94X3NR16R17, X3NR17C(O)R16, xe2x80x94X3NR17C(O)OR16, xe2x80x94X3C(O)NR16R17, xe2x80x94X3S(O)2NR16R17, xe2x80x94X3NR17C(O)NR16R17 or xe2x80x94X3NR17C(NR17)NR16R17, wherein X3, R16 and R17 are as defined above; wherein within R9 and/or R10 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR12R12, xe2x80x94X3NR12C(O)OR12, xe2x80x94X3NR12C(O)NR12R12, xe2x80x94X3NR12C(NR12)NR12R12, xe2x80x94X3OR12, xe2x80x94X3SR12, xe2x80x94X3C(O)OR12, xe2x80x94X3C(O)NR12R12, xe2x80x94X3S(O)2NR12R12, xe2x80x94X3P(O)(OR3)OR12, xe2x80x94X3OP(O)(OR3)OR12, xe2x80x94X3NR12C(O)R13, xe2x80x94X3S(O)R13, xe2x80x94X3S(O)2R13 and xe2x80x94X3C(O)R13, wherein X3, R12 and R13 are as defined above; or
R9 together with R7 and/or R10 together with R8 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo, (C1-4)alkyl or methylene; or
R9 and R5 together with the carbon atom to which both R9 and R5 are attached and/or R10 and R6 together with the carbon atom to which both R10 and R6 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene; and
R11 is xe2x80x94X4X5R18, wherein X4 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, X5 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR19xe2x80x94, wherein R19 is hydrogen or (C1-6)alkyl, and R18 is (i) (C1-6)alkyl optionally substituted by cyano, halo, halo-substituted (C1-3)alkyl, nitro, xe2x80x94NR14R14, xe2x80x94NR14C(O)OR14, xe2x80x94NR14C(O)NR14R14, xe2x80x94NR14C(NR14)NR14R14, xe2x80x94OR14, xe2x80x94SR14, xe2x80x94C(O)OR14, xe2x80x94C(O)NR14R14, xe2x80x94S(O)2NR14R14, xe2x80x94P(O)(OR14)OR14, xe2x80x94OP(O)(OR14)OR14, xe2x80x94NR14C(O)R15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(O)R20, xe2x80x94S(O)2R20, xe2x80x94C(O)R20, xe2x80x94C(O)OR20, xe2x80x94C(O)NR20R21, xe2x80x94NR20R21, xe2x80x94NR21C(O)R20, xe2x80x94NR21C(O)OR20, xe2x80x94NR21C(O)NR20R21 or xe2x80x94NR21C(NR21)NR20R21, wherein R14 and R15 are as defined above, R20 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12polycycloaryl(C0-6)alkyl and R21 at each occurrence independently is hydrogen or (C1-6)alkyl, or (ii) (C3-12)cycloalky(C0-6)alkyl, hetero(C3-12)Cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, diphenyl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, dihetero(C5-6)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl wherein said cycloalkyl, heterocycloalkyl, aryl, diphenyl, heteroaryl, diheteroaryl, polycycloaryl or heterpolycycloaryl ring may be substituted by xe2x80x94R22, xe2x80x94X3OR22, xe2x80x94X3SR22, xe2x80x94X3S(O)R22, xe2x80x94X3S(O)2R22, xe2x80x94X3C(O)R22, xe2x80x94X3C(O)OR22, xe2x80x94X3C(O)NR22R23, xe2x80x94X3NR22R23, xe2x80x94X3NR23C(O)R22, xe2x80x94X3NR23C(O)OR22, xe2x80x94X3NR23S(O)2R22, xe2x80x94X3NR23C(O)NR22R23 or xe2x80x94X3NR23C(NR23)NR22R23, wherein X3 is as defined above, R22 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl and R23 at each occurrence independently is hydrogen or (C1-6)alkyl; wherein within R11 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR12R12, xe2x80x94X3NR12C(O)OR12, xe2x80x94X3NR12C(O)NR12R12, xe2x80x94X3NR12C(NR12)NR12R12, xe2x80x94X3OR12, xe2x80x94X3SR12, xe2x80x94X3C(O)OR12, xe2x80x94X3C(O)NR12R12, xe2x80x94X3S(O)2NR12R12, xe2x80x94X3P(O)(OR3)OR12, xe2x80x94X3OP(O)(OR3)OR12, xe2x80x94X3NR12C(O)R13, xe2x80x94X3S(O)R13, xe2x80x94X3S(O)2R13 and xe2x80x94X3C(O)R13, wherein X3, R12 and R13 are as defined above;
R2 is hydrogen or (C1-6)alkyl;
R3 is hydrogen, (C1-6)alkyl or as defined below;
R4is (i) cyano, xe2x80x94C(O)OR12 or (C1-6)alkyl, wherein said alkyl optionally is substituted with cyano, halo, halo-substituted (C1-3)alkyl, nitro, xe2x80x94NR12R12, xe2x80x94NR12C(O)OR12, xe2x80x94NR12C(O)NR12R12, xe2x80x94NR12C(NR12)NR12R12, xe2x80x94OR12, xe2x80x94SR12, xe2x80x94C(O)OR12, OC(O)R12, xe2x80x94C(O)NR12R12, xe2x80x94S(O)2NR12R12, xe2x80x94P(O)(OR12)OR12, xe2x80x94OP(O)(OR12)OR12, xe2x80x94NR12C(O)R13, xe2x80x94S(O)R13, xe2x80x94S(O)2R13, xe2x80x94C(O)R13, OR14, xe2x80x94SR14, xe2x80x94S(O)R14, xe2x80x94S(O)2R14, xe2x80x94C(O)R14, xe2x80x94C(O)OR14, xe2x80x94OC(O)R14, xe2x80x94NR14R15, xe2x80x94NR15C(O)R14, xe2x80x94NR15C(O)OR14, xe2x80x94C(O)NR14R15, xe2x80x94S(O)2NR14R15, xe2x80x94NR15C(O)NR14R15 or xe2x80x94NR15C(NR15)NR14R15, wherein R12, R13 and R14 are as defined above, or (ii) a group selected from (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)Cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl and hetero(C8-12)polycycloaryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R16, xe2x80x94X3OR16, xe2x80x94X3SR16, xe2x80x94X3S(O)R16, xe2x80x94X3S(O)2R16, xe2x80x94X3C(O)R16, xe2x80x94X3C(O)OR16, xe2x80x94X3OC(O)R16, X3NR16R17, xe2x80x94X3NR17C(O)R16, xe2x80x94X3NR17C(O)OR16, xe2x80x94X3C(O)NR16R17, xe2x80x94X3S(O)2NR16R17, xe2x80x94X3NR17C(O)NR16R17 or xe2x80x94X3NR17C(NR17)NR16R17, wherein X3, R16 and R17 are as defined above; wherein within R4 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR12R12, xe2x80x94X3NR12C(O)OR12, xe2x80x94X3NR12C(O)NR12R12, xe2x80x94X3NR12C(NR12)NR12R12, xe2x80x94X3OR12, xe2x80x94X3SR12, xe2x80x94X3C(O)NR12R12, xe2x80x94X3S(O)2NR12R12, xe2x80x94X3P(O)(OR3)OR12, xe2x80x94X3OP(O)(OR3)OR12, xe2x80x94X3NR12C(O)R13, xe2x80x94X3S(O)R13, xe2x80x94X3S(O)2R13 and xe2x80x94X3C(O)R13, wherein X3, R12 and R13 are as defined above; or
R4 taken together with R2 forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo, (C1-4)alkyl or methylene; or
R4 and R3 taken together with the carbon atom to which both R4 and R3 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR12R12, xe2x80x94X3NR12C(O)OR12, xe2x80x94X3NR12C(O)NR12R12, xe2x80x94X3NR12C(NR12)NR12R12, xe2x80x94X3OR12, xe2x80x94X3SR12, xe2x80x94X3C(O)OR12, xe2x80x94X3C(O)NR12R12, xe2x80x94X3S(O)2NR12R12, xe2x80x94X3P(O)(OR3)OR12, xe2x80x94X3OP(O)(OR3)OR12, xe2x80x94X3NR12C(O)R13, xe2x80x94X3S(O)R13, xe2x80x94X3S(O)2R13 and xe2x80x94X3C(O)R13, wherein X3, R12 and R13 are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
A second aspect of the invention relates to compounds of Formula II: 
in which:
X1 is selected from xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94C(S), xe2x80x94S(O)2xe2x80x94 and xe2x80x94P(O)2xe2x80x94;
R1 and R2 independently are hydrogen or (C1-6)alkyl;
R3 and R4 independently are hydrogen or (C1-6)alkyl or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-8)cycloalkylene;
R5 and R6 independently are hydrogen or (C1-6)alkyl or R5 and R6 taken together with the carbon atom to which both R5 and R6 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene; and
R7 is xe2x80x94X2X3R9, wherein X2 is xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94P(O)2xe2x80x94, X3 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR10xe2x80x94, wherein R10 is hydrogen or (C1-6)alkyl, and R9 is (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alky), wherein within R9 said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by xe2x80x94R12, xe2x80x94X4NR11R12, xe2x80x94X4NR11C(O)R12, xe2x80x94X4NR11C(O)OR12, xe2x80x94X4NR11C(O)NR11R12, xe2x80x94X4NR11C(NR11)NR11R12, xe2x80x94X4OR12, xe2x80x94X4SR12, xe2x80x94X4S(O)R12, xe2x80x94X4S(O)2R12, xe2x80x94X4C(O)R12, xe2x80x94X4C(O)OR12, xe2x80x94X4OC(O)R12, xe2x80x94X4C(O)NR11R12, xe2x80x94X4OC(O)NR11R12, xe2x80x94X4S(O)2NR11R12, xe2x80x94X4P(O)(OR11)OR12 or xe2x80x94X4OP(O)(OR11)OR12, wherein X4 is a bond or (C1-6)alkylene, R11 at each occurrence is hydrogen or (C1-6)alkyl and R12 is (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl, wherein within R12 said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by xe2x80x94R13, xe2x80x94X4NR11R13, xe2x80x94X4NR11C(O)R13, xe2x80x94X4NR11C(O)OR13, xe2x80x94X4NR11C(O)NR11R13, xe2x80x94X4NR11C(NR11)NR11R13, xe2x80x94X4OR13, xe2x80x94X4SR13, xe2x80x94X4S(O)R13, xe2x80x94X4S(O)2R13, xe2x80x94X4C(O)R13, xe2x80x94X4C(O)OR13, xe2x80x94X4OC(O)R13, xe2x80x94X4C(O)NR11R13, xe2x80x94X4OC(O)NR11R13, xe2x80x94X4S(O)2NR11R13, xe2x80x94X4P(O)(OR11)OR13 or xe2x80x94X4OP(O)(OR11)OR13, wherein X4 and R11 are as defined above and R13 is (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl, wherein within R7 any alicyclic and aromatic rings present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR5)OR14, xe2x80x94X5OP(O)(OR5)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5 is a bond or (C1-6)alkylene, R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R15 is (C1-6)alkyl or halo-substituted (C1-3)alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
A third aspect of the invention is a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.
A fourth aspect of the invention is a method of treating a disease in an animal in which inhibition of a cysteine protease can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.
A fifth aspect of the invention is the processes for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivative, protected derivatives, individual isomers and mixtures of isomers, and the pharmaceutically acceptable salts thereof as set forth in xe2x80x9cDetailed Description of the Inventionxe2x80x9d.
Definitions
Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the meanings given this Section:
xe2x80x9cAlicyclicxe2x80x9d means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures having properties resembling those of aliphatics and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAliphaticxe2x80x9d means a moiety characterized by straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAlkylxe2x80x9d indicated alone means a straight or branched, saturated or unsaturated aliphatic radical having the number of carbon atoms indicated (e.g., (C1-6)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl indicated as part of a larger radical (e.g., as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when 0 atoms are indicated means a bond (e.g., (C0-3)alkyl of (C3-12)Cycloalkyl(C0-3)alkyl means a bond, methylene, ethylene, trimethylene, 1-methylethylene, or the like).
xe2x80x9cAlkylenexe2x80x9d, unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C1-6)alkylene includes methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), trimethylene (xe2x80x94CH2CH2CH2xe2x80x94), 2-methyltrimethylene (xe2x80x94CH2CH(CH3)CH2xe2x80x94), tetramethylene (xe2x80x94CH2CH2CH2CH2xe2x80x94), 2-butenylene (xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94), 2-methyltetramethylene (xe2x80x94CH2CH(CH3)CH2CH2xe2x80x94), pentamethylene (xe2x80x94CH2CH2CH2CH2CH2xe2x80x94) and the like). For example, the instance wherein R5 is hydrogen and R9 taken together with R7 forms optionally substituted trimethylene is illustrated by the following: 
in which R is an optional hydroxy or oxo group and X1 and R11 are as defined in the Summary of the Invention.
xe2x80x9cAlkylidenexe2x80x9d means a straight or branched saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C1-6)alkylidene includes methylene (xe2x95x90CH2), ethylidene (xe2x95x90CHCH3), isopropylidene (xe2x95x90C(CH3)2), propylidene (xe2x95x90CHCH2CH3), allylidene (xe2x95x90CHCHxe2x95x90CH2), and the like).
xe2x80x9cAminoxe2x80x9d means the radical xe2x80x94NH2. Unless indicated otherwise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
xe2x80x9cAnimalxe2x80x9d includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc.) and non-mammals (e.g., birds, etc.).
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic ring assembly (fused or linked by a single bond) containing the total number of ring carbon atoms indicated, wherein each ring is comprised of 6 ring carbon atoms and is aromatic or when fused with a second ring forms an aromatic ring assembly. For example,(C6-12)aryl includes phenyl, naphthyl and biphenylyl.
xe2x80x9cAromaticxe2x80x9d means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2.
xe2x80x9cCarbamoylxe2x80x9d means the radical xe2x80x94C(O)NH2. Unless indicated otherwise, the compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cCarboxyxe2x80x9d means the radical xe2x80x94C(O)OH. Unless indicated otherwise, the compounds of the invention containing carboxy moieties include protected derivatives thereof. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of annular carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C3-12)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthalenyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, etc.).
xe2x80x9cCycloalkylenexe2x80x9d means a saturated or partially unsaturated, monocyclic ring or bridged polycyclic ring assembly containing the number of annular carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, the instance wherein R9 and R5 together with the carbon atom to which both R9 and R5 are attached form (C3-8)cycloalkylenexe2x80x9d includes, but is not limited to, the following: 
in which X1 and R7 are as defined in the Summary of the Invention.
xe2x80x9cDiseasexe2x80x9d specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the xe2x80x9cside effectsxe2x80x9d of such therapy.
xe2x80x9cGuanidinoxe2x80x9d means the radical xe2x80x94NHC(NH)NH2. Unless indicated otherwise, the compounds of the invention containing guanidino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo.
xe2x80x9cHalo-substituted alkylxe2x80x9d, as a group or part of a group, means xe2x80x9calkylxe2x80x9d substituted by one or more xe2x80x9chaloxe2x80x9d atoms, as such terms are defined in this Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C1-3)alkyl includes chloromethyl, dicloromethyl, difluoromethyl, trifluromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like).
xe2x80x9cHeteroarylxe2x80x9d means aryl, as defined in this Application, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and each ring contained therein is comprised of 5 to 6 ring member atoms. For example, hetero(C5-12)aryl as used in this Application includes benzofuryl, benzooxazolyl, benzothiazolyl, [2,4xe2x80x2]bipyridinylyl, carbazolyl, carbolinyl, chromenyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuryl, isochromenyl, isooxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolyl, perimidinyl, 2-phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyradazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolizinyl, pyrrolidinyl, pyrrolyl, pyranyl, quinazolinyl, quinolizinyl, quinolyl, quinoxalinyl, tetrazolyl, thiazolyl, 4-thiazol4-ylphenyl, thienyl, xanthenyl, and the like. Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.
xe2x80x9cHeterocycloalkylxe2x80x9d means cycloalkyl, as defined herein, provided that one or more of the ring member carbon atoms indicated is replaced by heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)2, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. the term heterocyclo(C5-12)alkyl includes [1,4xe2x80x2]bipiperidinylyl, dihydrooxazolyl, morpholinyl, 1-morpholin-4-ylpiperidinyl, piperazinyl, piperidyl, pirazolidinyl, pirazolinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, and the like). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like. For example, a compound of Formula I wherein R1 is piperidin-4-ylcarbonyl may exist as either the unprotected or a protected derivative, e.g. wherein R1 is 1-tert-butoxycarbonylpiperidin-4-ylcarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cHeterocycloalkylenexe2x80x9d means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)2xe2x80x94, wherein R is hydrogen or (C1-6)alkyl. For example, the instance wherein R3 and R4 together with the carbon atom to which both R3 and R4 are attached form hetero(C3-8)Cycloalkylenexe2x80x9d includes, but is not limited to, the following: 
in which R is hydrogen, (C1-6)alkyl or a protecting group and R2 is as defined in the Summary of the invention.
xe2x80x9cHeteropolycycloarylxe2x80x9d means polycycloaryl, as defined herein, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)2xe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., hetero(C8-12)polycycloaryl includes 3,4-dihydro-2H-quinolinyl, 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H-[1,8]naphthyridinyl, morpholinylpyridyl, piperidinylphenyl, 1,2,3,4,5,6-hexahydro-[2,2xe2x80x2]bipyridinylyl, 2,4oxo-3,4-dihydro-2H -quinazolinyl, 3-oxo-2,3-dihydrobenzo[1,4]oxazinyl, etc.).
xe2x80x9cHeteroatom moietyxe2x80x9d includes xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)2xe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group.
xe2x80x9cHydroxyxe2x80x9d means the radical xe2x80x94OH. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like. For example, a compound of Formula I wherein the R9 contains a hydroxy moiety exist as either the unprotected or a protected derivative, e.g., wherein R9 is benzyloxybenzyl, and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cIminoketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(NR)xe2x80x94, wherein R is hydrogen or (C1-6)alkyl.
xe2x80x9cIsomersxe2x80x9d mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and stereoisomers that are nonsuperimposable mirror images are termed xe2x80x9cenantiomersxe2x80x9d or sometimes xe2x80x9coptical isomersxe2x80x9d. A carbon atom bonded to four nonidentical substituents is termed a xe2x80x9cchiral centerxe2x80x9d. A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a xe2x80x9cracemic mixturexe2x80x9d. A compound that has more than one chiral center has 2nxe2x88x921 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomers or as a mixture of diastereomers, termed a xe2x80x9cdiastereomeric mixturexe2x80x9d. When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 3rd edition, March, Jerry, John Wiley and Sons, New York, 1985). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to be encompassed all possible stereoisomers. Thus, for example, the name 1-(1-cyano-1-methylethylcarbamoyl)-3-methylbutylcarbamate is meant to include 1S-(1-cyano-1-methylethylcarbamoyl)-3-methylbutylcarbamate and 1R-(1-cyano-1-methylethylcarbamoyl)-3-methylbutylcarbamate and any mixture, racemic or otherwise, thereof.
xe2x80x9cKetone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(O)xe2x80x94.
xe2x80x9cMethylenexe2x80x9d means the divalent radical xe2x80x94CH2xe2x80x94 or CH2xe2x95x90, wherein its free valances can be attached to different atoms or the same atom. For example, the instance wherein R9 together with R7 forms trimethylene substituted methylene includes the following: 
in which X1 and R11 are as defined in the Summary of the invention, and may be referred to as 2,2-methylene and 1,2-methylene, respectively.
xe2x80x9cNitroxe2x80x9d means the radical xe2x80x94NO2.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase xe2x80x9cany 1 to 3 annular atoms of any aromatic ring with available valences comprising R6 optionally independently is substitutedxe2x80x9d means that the aromatic ring referred to may or may not be substituted in order to fall within the scope of the invention.
xe2x80x9cN-oxide derivativesxe2x80x9d means a derivatives of compound of Formula I in which nitrogens are in an oxidized state (i.e., O←N) and which possess the desired pharmacological activity.
xe2x80x9cOxoxe2x80x9d means the radical xe2x95x90O.
xe2x80x9cPathologyxe2x80x9d of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, ammonium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
xe2x80x9cPhenylene-1,2-dimethylenexe2x80x9d means the divalent radical xe2x80x94CH2C6H4CH2xe2x80x94, wherein the methylene moieties are attached at the 1- and 2-positions of the phenylene moiety. For example, a group of Formula (a), wherein R9 together with R7 form optionally substituted phenylene-1,2-dimethylene is illustrated by the following formula: 
in which R is an optional hydroxy or (C1-4)alkyl group and X1 and R11 are as defined in the Summary of the Invention.
xe2x80x9cPolycycloarylxe2x80x9d means a bicyclic ring assembly (directly linked by a single bond or fused) containing the number of ring member carbon atoms indicated, wherein at least one, but not all, of the fused rings comprising the radical is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C9-12)polycycloaryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthalenyl, and the like).
xe2x80x9cProdrug derivativesxe2x80x9d means derivatives of compounds of Formula I which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I.
xe2x80x9cProtected derivativesxe2x80x9d means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protecting groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active cysteine protease inhibitors. A comprehensive list of suitable protecting groups can be found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981.
xe2x80x9cTherapeutically effective amountxe2x80x9d means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
xe2x80x9cThioketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(S)xe2x80x94.
xe2x80x9cTreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any administration of a compound of the present invention and includes:
(1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,
(2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or
(3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
xe2x80x9cUreidoxe2x80x9d means the radical xe2x80x94NHC(O)NH2. Unless indicated otherwise, the compounds of the invention containing ureido moieties include protected derivatives thereof. Suitable protecting groups for ureido moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. For example, a compound of Formula I wherein the R9 contains an ureido moiety may exist as either the unprotected or a protected derivative and the like, and both the unprotected and protected derivatives fall within the scope of the invention.
Specific Embodiments
While the broadest definition of the invention is set forth in the Summary of the Invention, certain aspects of the invention are preferred. A preferred aspect of the invention are the compounds of Formula I in which:
R1 is a group Formula (a), wherein within Formula (a):
X1 is xe2x80x94C(O)xe2x80x94;
R5 is hydrogen, (C1-4)alkyl or as defined together with R9;
R7 is hydrogen, (C1-6)alkyl or as defined together with R9;
R9 is (i) (C1-6)alkyl optionally substituted with halo-substituted (C1-3)alkyl, xe2x80x94OR12, or xe2x80x94NR12C(NR12)NR12R12, wherein R12 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl, or (ii) (C6-12)aryl(C0-6)alkyl, or
R9 taken together with R7 forms trimethylene optionally substituted oxo, (C1-4)alkyl or methylene, or
R9 and R5 together with the carbon atom to which both R9 and R5 are attached form (C3-8)Cycloalkylene or (C3-8)heterocycloalkylene; and
R11 is xe2x80x94X4X5R18, wherein X4 is xe2x80x94C(O)xe2x80x94, X5 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94S(O)2xe2x80x94 and R18 is (i) (C1-6)alkyl optionally substituted by xe2x80x94C(O)NR20R21 or xe2x80x94NR21C(O)R20, wherein R20 is (C6-12)aryl(C0-6)alkyl and R21 at each occurrence independently is hydrogen or (C1-6)alkyl, or (ii) (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl, wherein said heterocycloalkyl, aryl, heteroaryl or heteropolycycloaryl ring may be substituted by xe2x80x94R22, xe2x80x94X3OR22, xe2x80x94X3NR22R23, xe2x80x94X3NR17C(O)R16, xe2x80x94X3NR23C(O)OR22, xe2x80x94X3NR23S(O)2R22, xe2x80x94X3S(O)2R22, xe2x80x94X3C(O)R22 or xe2x80x94X3NR23C(O)NR22R23, wherein X3 is a bond or (C1-6)alkylene, R22 is hetero(C3-12)cycloalkyl(C0-6)alkyl and R23 at each occurrence independently is hydrogen or (C1-6)alkyl; wherein within R11 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR12R12, xe2x80x94X3NR12C(O)OR12, xe2x80x94X3NR12C(O)NR12R12, xe2x80x94X3NR12C(NR12)NR12R12, xe2x80x94X3OR12, xe2x80x94X3SR12, xe2x80x94X3C(O)OR12, xe2x80x94X3C(O)NR12R12, xe2x80x94X3S(O)2NR12R12, xe2x80x94X3P(O)(OR3)OR12, xe2x80x94X3OP(O)(OR3)OR12, xe2x80x94X3NR12C(O)R13, xe2x80x94X3S(O)R13, xe2x80x94X3S(O)2R13 and xe2x80x94X3C(O)R13, wherein X3 is a bond or (C1-6)alkylene, R12 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R13 is (C1-6)alkyl or halo-substituted (C1-3)alkyl;
R3 is hydrogen, (C1-6)alkyl or as defined together with R4; and
R4 is (i) hydrogen, cyano, xe2x80x94C(O)OR12 or (C1-6)alkyl wherein said alkyl optionally is substituted with xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, wherein R12 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl, or (ii) (C6-10)aryl(C0-3)alkyl or
R4 taken together with R2 forms trimethylene or
R4 and R3 taken together with the carbon atom to which both R4 and R3 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene, wherein said (C3-8)cycloalkylene or (C3-8)heterocycloalkylene optionally is substituted with (C1-6)alkyl.
A preferred aspect of the invention are the compounds of Formula I in which:
R1 is a group Formula (a), wherein within Formula (a):
X1 is xe2x80x94C(O)xe2x80x94;
R5 is hydrogen or as defined together with R9;
R7 is hydrogen;
R9 is (i) (C1-6)alkyl or
R9 and R5 together with the carbon atom to which both R9 and R5 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene; and
R11 is xe2x80x94X4X5R18, wherein X4 is xe2x80x94C(O)xe2x80x94 and R18 is (C6-12)aryl(C0-6)alkyl or hetero(C5-12)aryl(C0-6)alkyl, wherein said aryl or heteroaryl ring may be substituted by xe2x80x94R22, xe2x80x94X3OR22, xe2x80x94X3NR22R23, xe2x80x94X3NR17C(O)R)16, xe2x80x94X3NR23C(O)OR22, xe2x80x94X3NR23S(O)2R22, xe2x80x94X3S(O)2R22, xe2x80x94X3C(O)R22 or xe2x80x94X3NR23C(O)NR22R23, wherein X3 is a bond or (C1-6)alkylene, R22 is hetero(C3-12)cycloalkyl(C0-6)alkyl and R23 at each occurrence independently is hydrogen or (C1-6)alkyl; wherein within R11 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR12R12, xe2x80x94X3NR12C(O)OR12, xe2x80x94X3NR12C(O)NR12R12, xe2x80x94X3NR12C(NR12)NR12R12, xe2x80x94X3OR12, xe2x80x94X3SR12, xe2x80x94X3C(O)OR12, xe2x80x94X3C(O)NR12R12, xe2x80x94X3S(O)2NR12R12, xe2x80x94X3P(O)(OR3)OR12, xe2x80x94X3OP(O)(OR3)OR12, xe2x80x94X3NR12C(O)R13, xe2x80x94X3S(O)R13, xe2x80x94X3S(O)2R13 and xe2x80x94X3C(O)R13, wherein X3 is a bond or (C1-6)alkylene, R12 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R13 is (C1-6)alkyl or halo-substituted (C1-3)alkyl;
R3 is hydrogen or as defined together with R4; and
R4 is (i) hydrogen or
R4 and R3 taken together with the carbon atom to which both R4 and R3 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene, wherein said (C3-8)cycloalkylene or (C3-8)heterocycloalkylene optionally is substituted with (C1-6)alkyl.
A preferred aspect of the invention are the compounds of Formula I in which:
R1 is a group Formula (a), wherein within Formula (a):
X1 is xe2x80x94C(O)xe2x80x94;
R5 is hydrogen or as defined together with R9;
R7 is hydrogen;
R9 is (i) (C1-6)alkyl or
R9 and R5 together with the carbon atom to which both R9 and R5 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene; and
R11 is xe2x80x94X4X5R18, wherein X4 is xe2x80x94C(O)xe2x80x94 and R18 is phenyl, wherein said phenyl ring may be substituted by xe2x80x94R22, xe2x80x94X3OR22, xe2x80x94X3NR22R23, xe2x80x94X3NR17C(O)R16, xe2x80x94X3NR23C(O)OR22, xe2x80x94X3NR23S(O)2R22, xe2x80x94X3S(O)2R22, xe2x80x94X3C(O)R22 or xe2x80x94X3NR23C(O)NR22R23, wherein X3 is a bond or (C1-6)alkylene, R22 is hetero(C3-12)cycloalkyl(C0-6)alkyl and R23 at each occurrence independently is hydrogen or (C1-6)alkyl; wherein within R11 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR12R12, xe2x80x94X3NR12C(O)OR12, xe2x80x94X3NR12C(O)NR12R12, xe2x80x94X3NR12C(NR12)NR12R12, xe2x80x94X3OR12, xe2x80x94X3SR12, xe2x80x94X3C(O)OR12, xe2x80x94X3C(O)NR12R12, xe2x80x94X3S(O)2NR12R12, xe2x80x94X3P(O)(OR3)OR12, xe2x80x94X3OP(O)(OR3)OR12, xe2x80x94X3NR12C(O)R13, xe2x80x94X3S(O)R13, xe2x80x94X3S(O)2R13 and xe2x80x94X3C(O)R13, wherein X3 is a bond or (C1-6)alkylene, R12 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R13 is (C1-6)alkyl or halo-substituted (C1-3)alkyl;
R3 is hydrogen or as defined together with R4; and
R4 is (i) hydrogen or
R4 and R3 taken together with the carbon atom to which both R4 and R3 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene, wherein said (C3-8)cycloalkylene or (C3-8)heterocycloalkylene optionally is substituted with (C1-6)alkyl.
Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups.
Further preferred are compounds of Formula I selected from a group consisting of:
N-[1-(cyanomethyl-carbamoyl)-3-methyl-butyl]-3-[3-(3-morpholin-4-yl-propyl)-ureido]-benzamide; and
N-[1-(cyanomethyl-carbamoyl)-3-methyl-butyl]-3-(3-pyridin-2-yl-ureido)-benzamide;
N-[1S-(cyanomethyl-carbamoyl)-3-methyl-butyl]4-(3-pyridin4-ylmethyl-ureido)-benzamide;
N-[1-(cyanomethyl-carbamoyl)-3-methyl-butyl]4-(3-piperidin-4-yl-ureido)-benzamide;
N-[1-S-(dicyanomethyl-carbamoyl)-3-methyl-butyl]-4-morpholin-4-yl-benzamide;
4-dimethylamino-piperidine-1-carboxylic acid {4-[1-(cyanomethyl-carbamoyl)3-methyl-butylcarbamoyl]-phenyl}-amide;
N-[1S-cyanomethylcarbamoyl-3-methylbutyl)-4-(4-methylpiperazin-1-yl)benzamide;
N-[1-cyanomethylcarbamoyl-3-methylbutyl-4-(2-guanidinothiazol-4-yl)]benzamide;
{4-[1-S-(cyanomethyl-carbamoyl)-3-methyl-butylcarbamoyl]-phenyl}-carbamic acid 3-pyridin-4-yl-propyl ester; and
N-[1-(cyanomethyl-carbamoyl)-3-methyl-butyl]-{-4-3-[2-(3H-imidazol-4-yl)-ethyl]-ureido}-benzamide.
A preferred aspect of the invention are the compounds of Formula II in which:
X1 is selected from xe2x80x94C(O)xe2x80x94;
R1 and R2 both are hydrogen;
R3 is isobutyl and R4 is hydrogen or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form cyclopropylene or cyclohexylene;
R5 and R6 both are hydrogen or R5 and R6 taken together with the carbon atom to which both R5 and R6 are attached form cyclohexylene or (C6)heterocycloalkylene; and
R7 is xe2x80x94X2X3R9, wherein X2 is xe2x80x94C(O)xe2x80x94, X3 is a bond and R9 is phenyl, wherein within R9 said phenyl is substituted by xe2x80x94R12, xe2x80x94X4NR11R12, xe2x80x94X4NR11C(O)R12, xe2x80x94X4NR11C(O)OR12, xe2x80x94X4NR11C(O)NR11R12, xe2x80x94X4NR11C(NR11)NR11R12, xe2x80x94X4OR12, xe2x80x94X4SR12, xe2x80x94X4S(O)R12, xe2x80x94X4S(O)2R12, xe2x80x94X4C(O)R12, xe2x80x94X4C(O)OR12, xe2x80x94X4OC(O)R12, xe2x80x94X4C(O)NR11R12, xe2x80x94X4OC(O)NR11R12, xe2x80x94X4S(O)2NR11R12, xe2x80x94X4P(O)(OR11)OR12 or xe2x80x94X4OP(O)(OR11)OR12, wherein X4 is a bond or (C1-6)alkylene, R11 at each occurrence is hydrogen or (C1-6)alkyl and R12 is hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl, wherein within R12 said heterocycloalkyl, phenyl or heteroaryl is substituted by xe2x80x94R13, xe2x80x94X4NR11R13, xe2x80x94X4NR11C(O)R13, xe2x80x94X4NR11C(O)OR13, xe2x80x94X4NR11C(O)NR11R13, xe2x80x94X4NR11C(NR11)NR11R13, xe2x80x94X4OR13, xe2x80x94X4SR13, xe2x80x94X4S(O)R13, xe2x80x94X4S(O)2R13, xe2x80x94X4C(O)R13, xe2x80x94X4C(O)OR13, xe2x80x94X4OC(O)R13, xe2x80x94X4C(O)NR11R13, xe2x80x94X4OC(O)NR11R13, xe2x80x94X4S(O)2NR11R13, xe2x80x94X4P(O)(OR11)OR13 or xe2x80x94X4OP(O)(OR11)OR13, wherein X4 and R11 are as defined above and R13 is (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(CO6)alkyl or hetero(C5-6)aryl(C0-6)alkyl, wherein within R7 any alicyclic and aromatic rings present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR5)OR14, xe2x80x94X5OP(O)(OR5)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5 is a bond or (C1-6)alkylene, R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R15 is (C1-6)alkyl or halo-substituted (C1-3)alkyl.
Further preferred are compounds of Formula II selected from a group consisting of:
N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-(2-pyrid-4-ylamino)thiazol-4-ylbenzamide;
4-[3-(1-benzylpiperidin-4-yl)ureido]-N-(1S-cyanomethylcarbamoyl-3-methylbutyl)benzamide;
N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]benzamide;
N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-(2-pyrid-4-ylthiazol-4-yl)benzamide;
4-[3-(1-benzylpyrrolidin-3S-yl)-3-methylureido]-N-(1S-cyanomethylcarbamoyl-3-methylbutyl)benzamide;
N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-(4-pyrid4-ylpiperazin-1-yl)benzamide;
N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-[2-(1-methylpyridin-4-ylamino)thiazol4-yl]benzamide;
N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-[2-(1-methylpyridin-4-yl)thiazol-4-yl]benzamide;
N-[(S)-1-(Cyanomethyl-carbamoyl)-3-methyl-but-3-enyl]-4-[2-(pyridin-4-ylamino)-thiazol-4-yl]-benzamide;
N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-[2-(1-allylpyrid-4-yl)thiazol-4-yl]benzamide;
N-(1S-Cyanomethylcarbamoyl-3-methylbutyl)-4-(2-piperidin-4ylaminothiazol-4-yl)benzamide;
N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-(2-piperazin-1-ylthiazol4-yl)benzamide;
N-(1S-cyanomethylcarbamoyl-3-methylbutyl)-4-[2-(4-methylpiperazin-1-yl)thiazol4-yl]benzamide;
N-[1S-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]-4-(2-piperazin-1-yl-thiazol-4-yl)benzamide;
N-[1S-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide;
N-[1S-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]-4-(2-piperidin-4-ylaminothiazol4-yl)benzamide;
N-(1-cyanomethylcarbamoylcyclohexyl)-4-(2-piperazin-1-ylthiazol4-yl)benzamide;
N-[1-(Cyanomethyl-carbamoyl)cyclohexyl]-4-[2-(piperidin-4-ylamino)-thiazol-4-yl]-benzamide;
N-(1R-cyanomethylcarbamoyl-3-methylbutyl)-4-(2-molpholin-4-ylthiazol4-yl)benzamide;
N-(1-Cyanomethylcarbamoylcyclohexyl]-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide;
N-[1-(4-cyanotetrahydropyran-4-ylcarbamoyl)cyclohexyl]-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide;
N-(1-cyanomethylcarbamoylcyclohexyl)-4-(2-morpholin-4-ylthiazol-4-yl)benzamide;
N-(1-cyanomethylcarbamoylcyclohexyl)-4-(2-piperazin-1-ylmethylthiazol-4-yl)benzamide;
tert-butyl 4-(4-{4-[1S-(1-cyanocyclopropylcarbamoyl)-3-methylbutylcarbamoyl]phenyl}thiazol-2-ylmethyl)piperazine-1-carboxylate;
N-[(S)-1-(1-Cyano-cyclopropylcarbamoyl)-3-methyl-butyl]-4-(2-piperazin-1-ylmethyl-thiazol-4-yl)-benzamide; and
N-(1S-cyanomethylcarbamoyl-3-methylbutyl]-4-(4-morpholin-4-ylmethylthiazol-2-ylamino)benzamide.
Pharmacology and Utility
The compounds of the invention are cysteine protease inhibitors, in particular the compounds of the invention inhibit the activity of cathepsins B, L, K and/or S and, as such, are useful for treating diseases in which cathepsin B, L, K and/or S activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the invention are useful in treating tumor invasion and metastasis, in particular as anti-angiogenic agents, rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders. Furthermore, the compounds of the invention are useful in treating bone resorption disorders, e.g., osteoporosis. The compounds of the invention also are useful in treating autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves"" disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto""s thyroiditis, allergic disorders, including, but not limited to asthma, and allogeneic immune responses, including, but not limited to, organ transplants or tissue grafts.
The cysteine protease inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Typically, the assay measures protease induced hydrolysis of a peptide based substrate. Details of assays for measuring protease inhibitory activity are set forth in Examples 10, 11, 12 and 13, infra.
Nomenclature
The compounds of Formula I and the intermediates and starting materials used in their preparation. The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc.. Alternatively, the compounds are named by AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, a compound of Formula I in which R1 is benzyloxycarbonylaminobutyryl and R2, R3 and R4 are each hydrogen; that is, a compound having the following structure: 
is named benzyl (S)-1-cyanomethylcarbamoyl-3-methylbutylcarbamate or [(S)-1-(cyanomethyl-carbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester; and a compound of Formula I in which R1 is 4-(2-meth-4-ylthiazolyl)benzoylaminobutyryl and R2, R3 and R4 are each hydrogen; that is, a compound having the following structure: 
is named N-(1-cyanomethylcarbamoyl-3-methylbutyl)-4-(2-methylthiazol-4-yl)benzamide or N-[(S)-1-(cyanomethyl-carbamoyl)-3-methyl-butyl]-4-(2-methyl-thiazol-4-yl)-benzamide; and a compound of Formula I in which R1 is 4-(2-meth-4-ylthiazolyl)benzoylaminobutyryl and R2, R3 and R4 are each hydrogen; that is, a compound having the following structure: 
is named ethyl 4-{4-[4-(1S-cyanomethylcarbamoyl-3-methylbutylcarbamoyl)phenyl]thiazol-2-ylamino}piperidine-1-carboxylate or 4-(4-{4-[(S)-1-(cyanomethyl-carbamoyl)-3-methyl-butylcarbamoyl]-phenyl}-thiazol-2-ylamino)-piperidine-1-carboxylic acid ethyl ester.
Administration and Pharmaceutical Compositions
In general, compounds of Formula I will be administered in therapeutically effective to amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I may range from 0.1 micrograms per kilogram body weight (xcexcg/kg) per day to 10 milligram per kilogram body weight (mglkg) per day, typically 1 xcexcg/kg/day to 1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 10 xcexcg/day to 100 mg/day, typically 0.1 mg/day to 10 mg/day. In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.
The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.
The amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of Formula I for treating a given disease will comprise from 0.01% w to 10% w, preferably 0.3% w to 1% w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of Formula I are described in Example 17.
The compounds of Formula I can be administered alone or in combination with other compounds of Formula I or in combination with one or more other active ingredient(s). For example, the compounds of Formula I can be administered in combination with a therapeutically active amount of a bisphosphonic acid or acid ester derivative or any pharmaceutically acceptable salt thereof. Suitable bisphosphonic acids and acid ester derivatives include compounds corresponding to the following formula: 
wherein X11 is a bond or (C1-7)alkylene, each R43 independently is hydrogen or (C1-30)alkyl, R44 and R45 are selected independently from a group consisting of hydrogen, halo, optionally substituted (C1-30)alkyl, (C3-30)cycloalkyl, hetero(C5-30)cycloalkyl, optionally substituted (C6-10)aryl, hetero(C6-10)aryl, xe2x80x94NR46R46, xe2x80x94OR46, xe2x80x94SR46, wherein each R46 independently is hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, optionally substituted (C6-10)aryl, provided that both R44 and R45 are not selected from hydrogen or hydroxy when X11 is a bond; or R44 and R45 taken together form (C2-9)alkylene; wherein (C3-10)cycloalkyl includes adamantyl and the like, hetero(C5-10)cycloalkyl includes pyrrolidinyl and the like, (C6-10)aryl includes phenyl and naphthyl, and hetero(C6-10)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like.
Instances wherein R44 and/or R45 are substituted (C1-30)alkyl may include, but are not limited to, (C1-30)alkyl substituted by hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C6-10)aryl, xe2x80x94NR47R47, xe2x80x94OR47 and xe2x80x94SR47, wherein each R47 is independently hydrogen or (C1-10)alkyl; wherein hetero(C5-10)cycloalkyl includes pyrrolidinyl and the like, (C6-10)aryl includes phenyl and naphthyl, and hetero(C6-10)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopylidyl and the like. Suitable optionally substituted aryl groups include, but are not limited to, halo-substituted phenyl.
A non-limiting class of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R44 is selected from the group consisting of hydrogen, hydroxy or halo, and R45 is selected from the group consisting of optionally substituted (C1-30)alkyl, halo and xe2x80x94SR46, wherein R46 is (C1-10)alkyl or phenyl.
A non-limiting subclass of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R44 is selected from the group consisting of hydrogen, hydroxy and chloro and R45 is selected from the group consisting of optionally substituted (C1-30)alkyl, chloro and chlorophenylthio.
A non-limiting example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I include that in which X11 is a bond, each R43 is hydrogen, R44 is hydroxy and R45 is 3-aminopropyl, namely 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (aka alendronic acid), or the monosodium trihydrate salt thereof, namely 4-amino-1-hydroxybutylidene-1,1-bisphosphonate monosodium trihydrate (aka alendronate monosodium trihydrate), described in U.S. Pat. No. 4,922,007, to Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651, to Kieczykowski et al., issued May 28, 1991; U.S. Pat. Nos. 5,510,517, to Dauer et al., issued Apr. 23, 1996; U.S. Pat. No. 5,648,491, to Dauer et al., issued Jul. 15, 1997, all of which patents are incorporated by reference herein in their entirety.
Further nonlimiting examples of bisphosphonic acids suitable for administration in combination with compounds of Formula I include the following:
cycloheptylaminomethylene-1,1-bisphosphonic acid (aka cimadronic acid), described in U.S. Pat. No. 4,970,335, to Isomura et al., issued Nov. 13, 1990;
1,1-dichloromethylene-1,1diphosphonic acid (aka clodronic acid) and the disodium salt thereof, namely clodronate disodium, described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967);
1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid (aka EB-1053);
1-hydroxyethylidene-1,1-diphosphonic acid (aka etidronic acid);
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid (aka ibandronic acid), described in U.S. Pat. No. 4,927,814, issued May 22, 1990;
6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (aka zolendronic acid);
3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid (aka olpadronic acid);
3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (aka pamidronic acid);
2-pyrid-2-ylethylidene-1,1-bisphosphonic acid (aka piridronic acid), described in U.S. Pat. No. 4,761,406;
1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid (aka risedronic acid);
4-chlorophenylthiomethylenebisphosphonic acid (aka tiludronic acid), described in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24, 1989; and
1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (aka zoledronic acid); all of which patents and other documents referred to above are incorporated by reference herein in their entirety.
A non-limiting subclass of bisphosphonic acids suitable for administration in combination with compounds of Formula I include those selected from the group consisting of alendronic acid, cimadronic acid, clodronic acid, tiludronic acid, etidronic acid, ibandronic acid, risedronic acid, piridronic acid, pamidronic acid, zolendronic acid, pharmaceutically acceptable salts thereof, and mixtures thereof. A further example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I is alendronic acid or a pharmaceutically acceptable salt thereof, and mixtures thereof. A further non-limiting example is alendronate monosodium trihydrate.
Compounds of Formula I can be administered in combination with a therapeutically active amount of an estrogen receptor agonist. Non-limiting examples of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include naturally occurring estrogens such as estradiol, estrone and estroil, or synthetic estrogen receptor agonists such as [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-(2-piperidin-1-ylethoxy)phenyl]methanone (aka raloxifene) and {2-[4-(1,2-diphenylbut-1-enyl)phenoxy]ethyl}dimethylamine (aka tamoxifen). A non-limiting subclass of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include estrogen receptor partial agonists (i.e., estrogen receptor agonists with mixed agonist/antagonist properties), sometimes referred to as estrogen receptor modulators. Estrogen receptor partial agonists can exert tissue-selective estrogen agonist effects. Tamoxifen, for example, selectively exerts an estrogen agonist effect on the bone, in humans. Additional suitable estrogen receptor partial agonists are described in Tissue-Selective Actions Of Estrogen Analogs, Bone Vol. 17, No. 4, October 1995, 181S-190S. Certain 3-[4-(2-phenylindol-1-ylmethyl)phenyl]acrylamides, described in U.S. Pat. No. 5,985,910 to Miller et al., Nov. 16, 1999; benzothiphene compounds, described in U.S. Pat. No. 5,985,897 to Meuhl et al., Nov. 16, 1999; naphthyl compounds, described in U.S. Pat. No. 5,952,350 to Cullinan et al., Sep. 14, 1999; substituted benzothiophene compounds, described in U.S. Pat. No. 5,962,475 to Schmid et al., Oct. 4, 1999, are suitable estrogen receptor partial agonists for administration with the compounds of Formula I; all of which patents and other documents referred to above are incorporated by reference herein in their entirety.
More particularly a pharmaceutical composition of this invention may comprise a therapeutically effect amount of a compound of Formula I in combination with one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effect amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effect amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipient(s). Non-limiting examples of such bisphosphonic acids include 1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid, 1-hydroxyethylidene-1,1-diphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid, 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof; particularly 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof and preferably 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.
Chemistry
Processes for Making Compounds of Formula I
Compounds of Formula I can be prepared by proceeding as in the following Scheme 1: 
in which Y is hydrogen or an activating group (e.g., 2,5-dioxopyrrolidin-1-yl (NBS), and the like) and each R1, R2, R3 and R4 are as defined in the Summary of the Invention.
Compounds of Formula I can be prepared by reacting a compound of Formula 2, or a protected derivative thereof, with a compound of the formula R1OY, or a protected derivative thereof, and then optionally deprotecting. The reaction is carried out in the presence of a suitable acylation catalyst (e.g., triethylamine) and in a suitable solvent (e.g., acetonitrile, N,N-dimethyformamide (DMF), methylene chloride, or any suitable combination thereof) at 10 to 30xc2x0 C., preferably at about 25xc2x0 C., and requires 24 to 30 hours to complete. When Y is hydrogen the reaction can be effected in the presence of a suitable coupling agent (e.g., benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP(copyright)), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or the like) and base (e.g., N,N-diisopropylethylamine, triethylamine, or the like) and requires 2 to 15 hours to complete. Alternatively, when Y is hydrogen the reaction can be carried out by treating the compound of formula R1OH with N-methylmorpholine and isobutyl chloroformate in a suitable solvent (e.g., TBF, or the like) at between 0 and 5xc2x0 C. for 30 minutes to an hour and then introducing the compound of Formula 2 to the reaction mixture and allowing the reaction to proceed for 12 to 15 hours.
Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981. A detailed description of the preparation of a compound of Formula I according to Scheme 1 is set forth in Examples 4, 5, 6 and 8, infra.
Alternatively, compounds of Formula I can be prepared by reacting a compound of Formula 2 with a compound of the formula R1-SS, wherein SS is a suitable solid support (e.g., thiophenol resin, or the like). The reaction can be carried out in the presence of a suitable acylation catalyst (e.g., 4-dimethylaminopyridine, or the like) and in a suitable solvent (e.g., dry pyrimidine, or the like) and requires 60 to 70 hours to complete. A detailed description of the preparation of a compound of Formula I according to the above-described procedures is set forth in Example 9 infra.
Compounds of Formula I can be prepared by proceeding as in the following reaction Scheme 2: 
in which each R1, R2, R3 and R4 are as defined in the Summary of the Invention.
Compounds of Formula I can be prepared by treating a compound of Formula 3, or a protected derivative thereof, with ammonia to provide a corresponding amide, then reacting the amide with a suitable dehydrating agent (e.g., trifluoroacetic anhydride, cyanuric chloride, thionyl chloride, phosphonyl chloride, and the like) and optionally deprotecting. The reaction with the ammonia is carried out in a suitable solvent (e.g., methanol) at between 0 and 5xc2x0 C. and requires 6 to 10 days to complete. The reaction with the dehydrating agent is carried out in the presence of a suitable base (e.g, triethylamine) and in a suitable solvent (e.g., tetrahydrofuran (THF), and the like) at between 0 and 50xc2x0 C. and requires 1 to 2 hours to complete. A detailed description of the preparation of a compound of Formula I according to Scheme 2 is set forth in Examples 7 and 8, infra.
Additional Processes for Preparing Compounds of Formula I
A compound of Formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of Formula I can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of Formula I in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). A compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at approximately 0xc2x0 C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80xc2x0 C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters. 4:1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, etc.).
Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981.
Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these disimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, Honh Wiley and Sons, Inc. (1981).
In summary, an aspect of the invention is a process for preparing a compound of Formula I, which process comprises:
(A) reacting a compound of Formula 2: 
xe2x80x83or a protected derivative thereof with a compound of the formula R1OY, or a protected derivative thereof, in which Y is hydrogen or an activating group and each R1, R2, R3 and R4 are as defined in the Summary of the Invention; or
(B) reacting a compound of Formula 3: 
xe2x80x83with ammonia to provide a corresponding amide and then reacting the amide with trifluoroacetic anhydride, in which each R1, R2, R3 and R4 are as defined in the Summary of the Invention
(C) optionally deprotecting a protected derivative of a compound of Formula I to provide a corresponding unprotected derivative;
(D) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;
(E) optionally converting a salt form of a compound of Formula I to non-salt form;
(F) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;
(G) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;
(H) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(I) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.
Processes for Preparing Intermediates
Compounds of Formula 2 can be prepared by reacting a compound of Formula 4: 
in which R19 is an amino protecting group and each R2, R3 and R4 are as defined in the Summary of the Invention, with thionyl chloride and then deprotecting. The reaction with the thionyl chloride is carried out in the presence of a suitable base (e.g, triethylamine) and in a suitable solvent (e.g, DMF) at between 0 and 5xc2x0 C. and requires 30 minutes to an hour to complete. Alternatively, compounds of Formula 2 can be prepared by reacting a compound of Formula 4 with trifluoroacetic anhydride. The deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield. A detailed description of the preparation of a compound of Formula 2 according to above-described procedure is set forth in Example 1, infra.
Compounds of Formula 4 can be prepared by treating a corresponding alkanoyl halide with ammonia. The treatment is carried out in a suitable solvent (e.g., dichloromethane, 5% aqueous sodium carbonate, and the like, or any suitable combination thereof) at 10 to 30xc2x0 C. and requires 30 minutes to an hour to complete. The alkanoyl halide intermediates can be prepared from the corresponding alkanoic acid by treating with thionyl chloride in a suitable solvent (e.g., dichloromethane) under nitrogen for 30 minutes to an hour. A detailed description of the preparation of a compound of Formula 2 according to the above-described procedures is set forth in Example 1, infra.
Compounds of the formula R1-SS can be prepared by reacting a compound of Formula 5(a) or 5(b): 
in which R19 is an amino protecting group (e.g., tert-butoxycarbonyl, fluoren-9-ylmethoxycarbonyl, or the like) and each X1, X2, X3, R5 and R7 are as defined for Formula I in the Summary of the Invention, with a suitable solid support resin (e.g, Wang (4-benzyloxybenzyl alcohol) resin, thiophenol resin, or the like), deprotecting to provide, respectively, a compound of Formula 6(a) or 6(b): 
in which SS is a solid support and then reacting the compound of Formula 6(a) or 6(b) with a compound of the formula R6OH (e.g., benzoic acid, indole-5-carboxylic acid, methanesulfonic acid, or the like).
The reaction between the compound of Formula 5(a) or 5(b) and the resin is carried out in the presence of a suitable coupling agent (e.g., benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (e.g., diisopropylcarbodiimide (DIC), PyBOP(copyright), EDC, HBTU, DCC, or the like) and acylation catalyst (e.g., N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, 1-hydroxybenzotriazole hydrate, or the like) in a suitable solvent (e.g., methylene chloride, DMF, or the like) and requires approximately 3 to 20 hours to complete. Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield. The reaction between the compound of Formula 6(a) or 6(b) is carried out with a suitable coupling agent and acylation catalyst. A detailed description of the preparation of a compound of the formula R1-SS according to the above-described procedures is set forth in Examples 2(A-C) and 4(A-C), infra.
Compounds of the formula R1OH can be prepared by treating a compound of formula R1-SS with a suitable acid (e.g., trifluoroacetic acid, or the like) in a suitable solvent (e.g, methylene chloride, or the like). Alternatively, compounds of the formula R1OH in which X1 is xe2x80x94C(O)xe2x80x94and X2 is xe2x80x94CHR9xe2x80x94 can be prepared by alkylating an organometallic compound of Formula 7(a) or 7(b): 
with a compound of the formula R9L, in which L is a leaving group and each X3, X4, R5, R6, R7 and R9 are as defined for Formula I in the Summary of the Invention, and then converting the resulting ethyl ester to the corresponding acid. The alkylation is carried out in a suitable solvent (e.g., THF) at xe2x88x9278xc2x0 C. to 0xc2x0 C. and requires 1 to 2 hours to complete. Conversion the acid can be effected by treating the ester with lithium hydroxide for approximately 15 hours. The organometallic compound is generated by treating a corresponding organo compound with an appropriate base (e.g., N,N-diisopropylethylamine, triethylamine, and the like) and n-butyllithium or tert-butyllithium at xe2x88x9280 to xe2x88x9270xc2x0 C., preferably at about xe2x88x9278xc2x0 C., for approximately 30 minutes to an hour. A detailed description of the preparation of a compound of the formula R1OH according to the above-described procedures is set forth in Example 3, infra.